PDBsum entry 2hrq

Hydrolase

PDB id: 2hrq

Contents

Protein chain

(+ 0 more) 532 a.a. *

Ligands

GLC-FRU ×6

GD7 ×6

NAG ×6

SIA ×6

SO4 ×12

Waters ×1115

* Residue conservation analysis

PDB id:

2hrq

Name:

Hydrolase

Title:

Crystal structure of human liver carboxylesterase 1 (hce1) in covalent complex with the nerve agent soman (gd)

Structure:

Liver carboxylesterase 1. Chain: a, b, c, d, e, f. Synonym: acyl coenzyme a:cholesterol acyltransferase, acat, monocyte/macrophage serine esterase, hmse, serine esterase 1, brain carboxylesterase hbr1, triacylglycerol hydrolase, tgh, egasyn. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ces1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.70Å R-factor: 0.170 R-free: 0.225

Authors:

C.D.Fleming,M.R.Redinbo

Key ref:

C.D.Fleming et al. (2007). Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun. Biochemistry, 46, 5063-5071. PubMed id: 17407327

Date:

20-Jul-06 Release date: 01-May-07

Protein chains

P23141  (EST1_HUMAN) -  Liver carboxylesterase 1 from Homo sapiens

Seq: 567 a.a.

Struc: 532 a.a.

Enzyme reactions

• Enzyme class 2: E.C.3.1.1.1 - carboxylesterase.
• Reaction: a carboxylic ester + H2O = an alcohol + a carboxylate + H⁺
• Enzyme class 3: E.C.3.1.1.13 - sterol esterase.
• Reaction: a sterol ester + H2O = a sterol + a fatty acid + H⁺
• Enzyme class 4: E.C.3.1.1.56 - methylumbelliferyl-acetate deacetylase.
• Reaction: 4-methylumbelliferyl acetate + H2O = 4-methylumbelliferone + acetate + H⁺

4-methylumbelliferyl acetate + H2O = 4-methylumbelliferone (Bound ligand (Het Group name = SIA) matches with 54.55% similarity) + acetate + H(+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Biochemistry 46:5063-5071 (2007)

PubMed id: 17407327

Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun.

C.D.Fleming, C.C.Edwards, S.D.Kirby, D.M.Maxwell, P.M.Potter, D.M.Cerasoli, M.R.Redinbo.

ABSTRACT

The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective, and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 A resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acyl-enzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 10(4)-fold more lethal PS stereoisomer of soman relative to the PR form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to dead-end organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure.